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1.  Association between Peripheral Oxidative Stress and White Matter Damage in Acute Traumatic Brain Injury 
BioMed Research International  2014;2014:340936.
The oxidative stress is believed to be one of the mechanisms involved in the neuronal damage after acute traumatic brain injury (TBI). However, the disease severity correlation between oxidative stress biomarker level and deep brain microstructural changes in acute TBI remains unknown. In present study, twenty-four patients with acute TBI and 24 healthy volunteers underwent DTI. The peripheral blood oxidative biomarkers, like serum thiol and thiobarbituric acid-reactive substances (TBARS) concentrations, were also obtained. The DTI metrics of the deep brain regions, as well as the fractional anisotropy (FA) and apparent diffusion coefficient, were measured and correlated with disease severity, serum thiol, and TBARS levels. We found that patients with TBI displayed lower FAs in deep brain regions with abundant WMs and further correlated with increased serum TBARS level. Our study has shown a level of anatomic detail to the relationship between white matter (WM) damage and increased systemic oxidative stress in TBI which suggests common inflammatory processes that covary in both the peripheral and central reactions after TBI.
PMCID: PMC3996315  PMID: 24804213
2.  Peripheral Leukocyte Apoptosis in Patients with Parkinsonism: Correlation with Clinical Characteristics and Neuroimaging Findings 
BioMed Research International  2014;2014:635923.
Apoptosis of both brain neurons and peripheral blood leukocyte is believed to be an important biomarker for evaluating the functional status of Parkinson's disease (PD). However, their correlation remains unknown. A better understanding of the pathophysiology of neurodegeneration is essential for the treatment and prevention of PD. The present study demonstrated that leukocyte apoptosis is significantly higher in PD patients and is associated with central dopamine neuron loss by using 99mTc-TRODAT-1 SPECT. The leukocyte apoptosis and striatal dopamine transporter uptake ratios were further associated with increased severity and longer duration of disease. The interaction between brain and systemic inflammation may be responsible for the neurodegenerative disease progression.
PMCID: PMC3984850  PMID: 24795890
3.  Diffusion Tensor Imaging Study of White Matter Damage in Chronic Meningitis 
PLoS ONE  2014;9(6):e98210.
Tuberculous meningitis (TBM) and cryptococcal meningitis (CM) are two of the most common types of chronic meningitis. This study aimed to assess whether chronic neuro-psychological sequelae are associated with micro-structure white matter (WM) damage in HIV-negative chronic meningitis. Nineteen HIV-negative TBM patients, 13 HIV-negative CM patients, and 32 sex- and age-matched healthy volunteers were evaluated and compared. The clinical relevance of WM integrity was studied using voxel-based diffusion tensor imaging (DTI) magnetic resonance imaging. All of the participants underwent complete medical and neurologic examinations, and neuro-psychological testing. Differences in DTI indices correlated with the presence of neuro-psychological rating scores and cerebrospinal fluid (CSF) analysis during the initial hospitalization. Patients with CM had more severe cognitive deficits than healthy subjects, especially in TBM. There were changes in WM integrity in several limbic regions, including the para-hippocampal gyrus and cingulate gyrus, and in the WM close to the globus pallidus. A decline in WM integrity close to the globus pallidus and anterior cingulate gyrus was associated with worse CSF analysis profiles. Poorer DTI parameters directly correlated with worse cognitive performance on follow-up. These correlations suggest that WM alterations may be involved in the psychopathology and pathophysiology of co-morbidities. Abnormalities in the limbic system and globus pallidus, with their close relationship to the CSF space, may be specific biomarkers for disease evaluation.
PMCID: PMC4043527  PMID: 24892826
4.  The Roles of Biomarkers of Oxidative Stress and Antioxidant in Alzheimer's Disease: A Systematic Review 
BioMed Research International  2014;2014:182303.
Purpose. Oxidative stress plays an important role in the pathogenesis of Alzheimer's disease (AD). This paper aims to examine whether biomarkers of oxidative stress and antioxidants could be useful biomarkers in AD, which might form the bases of future clinical studies. Methods. PubMed, SCOPUS, and Web of Science were systematically queried to obtain studies with available data regarding markers of oxidative stress and antioxidants from subjects with AD. Results and Conclusion. Although most studies show elevated serum markers of lipid peroxidation in AD, there is no sufficient evidence to justify the routine use of biomarkers as predictors of severity or outcome in AD.
PMCID: PMC4053273  PMID: 24949424
5.  Association between Oxidative Stress and Outcome in Different Subtypes of Acute Ischemic Stroke 
BioMed Research International  2014;2014:256879.
Objectives. This study investigated serum thiobarbituric acid-reactive substances (TBARS) and free thiol levels in different subtypes of acute ischemic stroke (AIS) and evaluated their association with clinical outcomes. Methods. This prospective study evaluated 100 AIS patients, including 75 with small-vessel and 25 with large-vessel diseases. Serum oxidative stress (TBARS) and antioxidant (thiol) were determined within 48 hours and days 7 and 30 after stroke. For comparison, 80 age- and sex-matched participants were evaluated as controls. Results. Serum TBARS was significantly higher and free thiol was lower in stroke patients than in the controls on days 1 and 7 after AIS. The level of free thiol was significantly lower in the large-vessel disease than in the small-vessel disease on day 7 after stroke. Using the stepwise logistic regression model for potential variables, only stroke subtype, NIHSS score, and serum TBARS level were independently associated with three-month outcome. Higher TBARS and lower thiol levels in the acute phase of stroke were associated with poor outcome. Conclusions. Patients with large-vessel disease have higher oxidative stress but lower antioxidant defense compared to those with small-vessel disease after AIS. Serum TBARS level at the acute phase of stroke is a potential predictor for three-month outcome.
PMCID: PMC4034452  PMID: 24895559
6.  Elevated Serum Vascular Cell Adhesion Molecule-1 Is Associated with Septic Encephalopathy in Adult Community-Onset Severe Sepsis Patients 
BioMed Research International  2014;2014:598762.
Background and Aim. Septic encephalopathy (SE) is a common complication of severe sepsis. Increased concentrations of circulating soluble adhesion molecules are reported in septic patients. This study aimed to determine whether serum adhesion molecules are associated with SE. Methods. Seventy nontraumatic, nonsurgical adult patients with severe sepsis admitted through ER were evaluated. Serum adhesion molecules were assessed for their relationship with SE, and compared with other clinical predictors and biomarkers. Results. Twenty-three (32.8%) patients had SE. SE group had higher in-hospital mortality (40% versus 11%, P = 0.009) and their sVCAM-1, sICAM-1, and lactate levels on admission were also higher than non-SE group. By stepwise logistic regression model, sVCAM-1, age, and maximum 24-hours SOFA score were independently associated with septic encephalopathy. The AUC analysis of ROC curve of different biomarkers showed that sVCAM-1 is better to predict SE. The sVCAM-1 levels in the SE group were significantly higher than those of the non-SE group at three time periods (Days 1, 4, and 7). Conclusions. Septic encephalopathy implies higher mortality in nontraumatic, nonsurgical patients with severe sepsis. VCAM-1 level on presentation is a more powerful predictor of SE in these patients than lactate concentration and other adhesion molecules on admission.
PMCID: PMC4032707  PMID: 24883317
7.  The Association among Antioxidant Enzymes, Autoantibodies, and Disease Severity Score in Systemic Lupus Erythematosus: Comparison of Neuropsychiatric and Nonneuropsychiatric Groups 
BioMed Research International  2014;2014:137231.
Background. Antioxidative capacity plays an important role in the severity of systemic lupus erythematosus (SLE), which is characterized by autoantibodies. This study aimed to determine the relationship among autoantibody titers, antioxidative stress reserve, and severity of SLE. Methods. The autoantibody titers, clinical markers, antioxidant enzyme levels, and disease activity index (SLEDAI-2k) of 32 SLE patients and 16 healthy controls were compared. We also compared both the neuropsychiatric (NPSLE) and nonneuropsychiatric (non-NPSLE) groups. Results. Superoxide dismutase in red blood cells was significantly lower in the SLE than in the control group. CRP levels are significant higher in SLE patients than in control group (P = 0.034). Among the autoantibodies, anti-U1RNP (P = 0.008), a-Sm (P = 0.027), and anti-ribosomal p (P = 0.028) significantly negatively correlated with glutathione levels. There has no significant correlation between SLE disease activity indexes (SLEDAI) and levels of C3, C4, and antioxidant enzymes. Conclusions. Erythrocyte superoxide dismutase is significantly lower in both NPSLE and non-NPSLE groups. SLE patients have both higher CRP and autoantibodies level and decreased superoxide dismutase level than the healthy control group.
PMCID: PMC4024413  PMID: 24877055
8.  The Association between Autoantibodies and Peripheral Neuropathy in Lupus Nephritis 
BioMed Research International  2014;2014:524940.
Background and Aim. The sensitivity and specificity of biomarkers used for predicting peripheral neuropathy in patients with systemic lupus erythematosus (SLE) and nephritis (SLE-LN) remain unsatisfactory. This study aimed to determine the autoantibodies levels in SLE-LN patients with peripheral neuropathy. Methods. Data of 559 SLE-LN patients were collected retrospectively, including titers of autoantibodies, electrodiagnostic studies, and clinical manifestations. Results. The neurologic manifestations of the SLE-LN patients were diverse and nonspecific. The prevalence rate of peripheral polyneuropathy was 2.68%, of which about 73.33% was mixed sensory-motor polyneuropathy. Numbness and functional gastrointestinal problems were the most prevalent symptoms and these were noted in every subtype of peripheral neuropathy. Among all the serology markers, anti-Ro was significantly associated with neuropathy related to SLE (P = 0.009). Conclusion. Peripheral neuropathy among LN patients is rare and may be easily overlooked. This study demonstrated that positive anti-Ro antibody may imply neuropathy in LN patients. Thus, anti-Ro can be considered a biomarker that should be added to the panel of conventional autoantibodies in LN patients.
PMCID: PMC4017733  PMID: 24864250
9.  Effects of Metformin on the Cerebral Metabolic Changes in Type 2 Diabetic Patients 
The Scientific World Journal  2014;2014:694326.
Metformin, a widely used antidiabetic drug, has numerous effects on human metabolism. Based on emerging cellular, animal, and epidemiological studies, we hypothesized that metformin leads to cerebral metabolic changes in diabetic patients. To explore metabolism-influenced foci of brain, we used 2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography for type 2 diabetic patients taking metformin (MET, n = 18), withdrawing from metformin (wdMET, n = 13), and not taking metformin (noMET, n = 9). Compared with the noMET group, statistical parametric mapping showed that the MET group had clusters with significantly higher metabolism in right temporal, right frontal, and left occipital lobe white matter and lower metabolism in the left parahippocampal gyrus, left fusiform gyrus, and ventromedial prefrontal cortex. In volume of interest (VOI-) based group comparisons, the normalized FDG uptake values of both hypermetabolic and hypometabolic clusters were significantly different between groups. The VOI-based correlation analysis across the MET and wdMET groups showed a significant negative correlation between normalized FDG uptake values of hypermetabolic clusters and metformin withdrawal durations and a positive but nonsignificant correlation in the turn of hypometabolic clusters. Conclusively, metformin affects cerebral metabolism in some white matter and semantic memory related sites in patients with type 2 diabetes.
PMCID: PMC3982461  PMID: 24782665
10.  Statin therapy reduces oxidized low density lipoprotein level, a risk factor for stroke outcome 
Critical Care  2014;18(1):R16.
Statins are reported to have anti-inflammatory and anti-oxidative effects aside from cholesterol-lowering effects. This study aimed to evaluate the effects of statin therapy on oxidized LDL (Ox-LDL) and the clinical outcome of patients with acute ischemic stroke (AIS).
This prospective study enrolled 120 patients with AIS divided in the statin (n = 55) and non-statin (n = 65) groups. Eighty sex- and age- matched participants were recruited as risk controls. Ox-LDL was measured using a monoclonal antibody-based enzyme-linked immune-sorbent assay at different time points after AIS. The clinical outcomes were analyzed between the statin and non-statin groups.
Plasma Ox-LDL was significantly higher in stroke patients than in the controls (P < 0.001). Plasma Ox-LDL level was significantly reduced in the statin group on day 7 and day 30 compared to the non-statin group (P < 0.01). The plasma Ox-LDL positively correlated with serum total cholesterol, LDL-cholesterol, and hemoglobin A1c (HbA1c). Among the potential risk factors, only National Institutes of Health stroke scale (NIHSS) score and Ox-LDL level on admission were independently associated with 3-month outcome.
Our study demonstrates that statin therapy reduces plasma Ox-LDL level after AIS. Plasma Ox-LDL may be a more powerful predictor than serum LDL, high-sensitivity C-reactive protein or white blood cell counts for stroke outcome. Therefore, assay of plasma Ox-LDL should be added as a predictor among the panel of conventional biomarkers in stroke outcome.
PMCID: PMC4056016  PMID: 24423248
11.  Long-term effects on carotid intima-media thickness after radiotherapy in patients with nasopharyngeal carcinoma 
Vascular abnormalities are the predominant histologic changes associated with radiation in nasopharyngeal carcinoma (NPC). This study examined if the duration after radiotherapy correlates with the progression of carotid intima-media thickness (IMT) and investigated its relationship with inflammatory markers.
One hundred and five NPC patients post-radiotherapy for more than one year and 25 healthy control subjects were examined by B-mode ultrasound for IMT measurement at the far wall of the common carotid artery (CCA). Surrogate markers including lipid profile, HbA1c, and high sensitive C-reactive protein (hs-CRP) were assessed.
The IMT of CCA was significantly increased in NPC patients and carotid plaque was detected in 38 NPC patients (38/105, 36.2%). Significant risk factors for carotid plaques included age, duration after radiotherapy, and HbA1c levels. Age, duration after radiotherapy, hs-CRP, HbA1c, and platelet count positively correlated with IMT. The cut-off value of age and duration after radiotherapy for the presence of plaque was 52.5 years and 42.5 months, respectively. In NPC subjects, multiple linear regression analysis revealed that age, gender, duration after radiotherapy and platelet counts were independently associated with CCA IMT. After adjustments for age, gender and platelet counts, IMT increased in a linear manner with duration after radiotherapy.
Radiation-induced vasculopathy is a dynamic and progressive process due to late radiation effects. Extra-cranial color-coded duplex sonography can be part of routine follow-up in NPC patients aged ≥50 years at 40 months post-radiotherapy.
PMCID: PMC3827874  PMID: 24196030
Atherosclerosis; Nasopharyngeal carcinoma; Radiotherapy; Risk factors
12.  The association among leukocyte apoptosis, autoantibodies and disease severity in systemic lupus erythematosus 
Both apoptosis and autoantibodies are important factors associated with disease activity in the pathogenesis of systemic lupus erythematosus (SLE). This study tested the hypothesis that increased leukocyte apoptosis is associated with elevated levels of autoantibodies and the disease activity of SLE.
Leukocyte apoptosis was determined by flow cytometry, including annexin V, APO2.7, and 7-amino-actinomycin D (7-AAD) on each subtype of leukocyte in 23 patients with SLE. Leukocyte apoptosis was also evaluated in nine patients with Sjogren’s syndrome (SJS) and in 20 volunteer subjects. Titers of common autoantibodies and the disease activity index (SLEDAI-2 k) of the SLE patients were also determined.
Except for annexin V and APO 2.7 of monocytes and late apoptosis (annexin V + 7-ADD) of lymphocytes, apoptosis in the total and in subsets of leukocytes were significantly higher in SLE patients than in controls (all p < 0.05, post hoc analysis). The mean percentage of late apoptosis of leukocytes (annexin V + 7-AAD) positively correlated with levels of anti-Ro52/60 (r = 0.513, p < 0.01), anti-La (r = 0.439, p = 0.04), and anti-Mi-2 (r = 0.492, p = 0.02), and inversely correlated with both C3 and C4 levels, although not statistically significant. The percentage of APO2.7 of CD19+ cells positively correlated with SLEDAI-2 K score (p = 0.01).
Leukocyte apoptosis is significantly higher in patients with SLE and correlates well with the levels of several autoantibodies. The APO2.7 of B-lymphocyte (CD19+) cells positively correlates with the disease activity of SLE.
PMCID: PMC3853096  PMID: 24138706
Autoantibodies; Diseases severity score; Leukocyte apoptosis; Systemic lupus erythematosus
13.  Structural and cognitive deficits in chronic carbon monoxide intoxication: a voxel-based morphometry study 
BMC Neurology  2013;13:129.
Patients with carbon monoxide (CO) intoxication may develop ongoing neurological and psychiatric symptoms that ebb and flow, a condition often called delayed encephalopathy (DE). The association between morphologic changes in the brain and neuropsychological deficits in DE is poorly understood.
Magnetic resonance imaging and neuropsychological tests were conducted on 11 CO patients with DE, 11 patients without DE, and 15 age-, sex-, and education-matched healthy subjects. Differences in gray matter volume (GMV) between the subgroups were assessed and further correlated with diminished cognitive functioning.
As a group, the patients had lower regional GMV compared to controls in the following regions: basal ganglia, left claustrum, right amygdala, left hippocampus, parietal lobes, and left frontal lobe. The reduced GMV in the bilateral basal ganglia, left post-central gyrus, and left hippocampus correlated with decreased perceptual organization and processing speed function. Those CO patients characterized by DE patients had a lower GMV in the left anterior cingulate and right amygdala, as well as lower levels of cognitive function, than the non-DE patients.
Patients with CO intoxication in the chronic stage showed a worse cognitive and morphologic outcome, especially those with DE. This study provides additional evidence of gray matter structural abnormalities in the pathophysiology of DE in chronic CO intoxicated patients.
PMCID: PMC3850907  PMID: 24083408
Carbon monoxide intoxication; Cognitive deficits; Delayed encephalopathy; Magnetic resonance imaging; Voxel-based morphometry
14.  The diagnostic value of ultrasonography in carpal tunnel syndrome: a comparison between diabetic and non-diabetic patients 
BMC Neurology  2013;13:65.
To compare the value of ultrasonography for diagnosing carpal tunnel syndrome (CTS) in patients with and without diabetes mellitus (DM).
Eighty non-DM and 40 DM patients with electromyography-confirmed CTS were assessed and underwent high-resolution ultrasonography of the wrists. Cross-sectional area (CSA) and flattening ratio (FR) of the median nerve were measured at the carpal tunnel outlet (D) and wrist crease (W).
The 80 non-DM and 40 DM patients had 81 and 59 CTS-hands, respectively. The CSA_D and CSA_W were significantly larger in the CTS-hands and DM-CTS-hands compared to the normal control (p < 0.001). However, there is no difference of CSA_D and CSA_W between DM and non-DM CTS patients. Receiver operating characteristics [ROC] curve analysis revealed that CSA_W ≥13 mm2 was the most powerful predictor of CTS in DM (area under curve [AUC] = 0.72; sensitivity 72.9%, specificity 61.9%) and non-DM (AUC = 0.72; sensitivity 78.5%, specificity 53.2%) patients. The CSA positively correlated with the distal motor latency of the median compound motor action potential (CMAP), distal sensory latency of the median sensory nerve action potential (SNAP), and latency of the median F wave, but negatively correlated with the amplitude of the median CMAP, amplitude of the median SNAP, and sensory NCV of the median nerve. Stepwise logistic regression revealed that CSA_W (OR 1.21, 95% CI 1.07-1.38; p = 0.003) was independently associated with CTS in DM patients and any 1 mm2 increase in CSA_W increased the rate of CTS by 28%.
The CSA of the median nerve at the outlet and wrist crease are significantly larger in CTS hands in both DM and non-DM patients compared to normal hands. The CSA of the median nerve by ultrasonography may be a diagnostic tool for evaluating CTS in DM and non-DM patients.
PMCID: PMC3697998  PMID: 23800072
Carpal tunnel syndrome; Cross-sectional area; Median nerve; Ultrasonography
15.  Bacterial brain abscess in patients with nasopharyngeal carcinoma following radiotherapy: microbiology, clinical features and therapeutic outcomes 
BMC Infectious Diseases  2012;12:204.
This study aimed to analyze the clinical features, causative pathogens, neuro-imaging findings, and therapeutic outcomes of bacterial brain abscess in patients with nasopharyngeal carcinoma (NPC) following radiotherapy.
NPC patients with bacterial brain abscess were evaluated. Their clinical data were collected over a 22-year period. For comparison, the clinical features, causative pathogens, neuro-imaging findings, and therapeutic outcomes between NPC and non-NPC patients were analyzed.
NPC accounted for 5.7% (12/210) of the predisposing factors, with Viridans streptococci and Staphylococcus aureus as the two most common causative pathogens. Significant statistical analysis between the two groups (NPC and non-NPC patients) included chronic otitis media (COM) as the underlying disease, post-radiation necrosis by neuro-imaging, and the temporal lobe as the most common site of brain abscesses. The fatality rate in patients with and without NPC was 16.7% and 20.7%, respectively.
NPC patients with bacterial brain abscess frequently have COM as the underlying disease. Neuro-imaging often reveals both post-radiation necrosis and the temporal lobe as the most common site of brain abscesses, the diagnosis of which is not always a straightforward process. Radiation necrosis can mimic brain abscess on neuro-imaging and pose significant diagnostic challenges. Early diagnosis and treatment is essential for survival.
PMCID: PMC3482557  PMID: 22943134
Bacterial brain abscess; Nasopharyngeal carcinoma; Therapeutic outcome
16.  Is there a role of whole-body bone scan in patients with esophageal squamous cell carcinoma 
BMC Cancer  2012;12:328.
Correct detection of bone metastases in patients with esophageal squamous cell carcinoma is pivotal for prognosis and selection of an appropriate treatment regimen. Whole-body bone scan for staging is not routinely recommended in patients with esophageal squamous cell carcinoma. The aim of this study was to investigate the role of bone scan in detecting bone metastases in patients with esophageal squamous cell carcinoma.
We retrospectively evaluated the radiographic and scintigraphic images of 360 esophageal squamous cell carcinoma patients between 1999 and 2008. Of these 360 patients, 288 patients received bone scan during pretreatment staging, and sensitivity, specificity, positive predictive value, and negative predictive value of bone scan were determined. Of these 360 patients, surgery was performed in 161 patients including 119 patients with preoperative bone scan and 42 patients without preoperative bone scan. Among these 161 patients receiving surgery, 133 patients had stages II + III disease, including 99 patients with preoperative bone scan and 34 patients without preoperative bone scan. Bone recurrence-free survival and overall survival were compared in all 161 patients and 133 stages II + III patients, respectively.
The diagnostic performance for bone metastasis was as follows: sensitivity, 80%; specificity, 90.1%; positive predictive value, 43.5%; and negative predictive value, 97.9%. In all 161 patients receiving surgery, absence of preoperative bone scan was significantly associated with inferior bone recurrence-free survival (P = 0.009, univariately). In multivariate comparison, absence of preoperative bone scan (P = 0.012, odds ratio: 5.053) represented the independent adverse prognosticator for bone recurrence-free survival. In 133 stages II + III patients receiving surgery, absence of preoperative bone scan was significantly associated with inferior bone recurrence-free survival (P = 0.003, univariately) and overall survival (P = 0.037, univariately). In multivariate comparison, absence of preoperative bone scan was independently associated with inferior bone recurrence-free survival (P = 0.009, odds ratio: 5.832) and overall survival (P = 0.029, odds ratio: 1.603).
Absence of preoperative bone scan was significantly associated with inferior bone recurrence-free survival, suggesting that whole-body bone scan should be performed before esophagectomy in patients with esophageal squamous cell carcinoma, especially in patients with advanced stages.
PMCID: PMC3443043  PMID: 22853826
Radionuclide imaging; Esophageal cancer; Squamous cell carcinoma; Metastasis; Esophagectomy
17.  Predictors and outcomes of shunt-dependent hydrocephalus in patients with aneurysmal sub-arachnoid hemorrhage 
BMC Surgery  2012;12:12.
Hydrocephalus following spontaneous aneurysmal sub-arachnoid hemorrhage (SAH) is often associated with unfavorable outcome. This study aimed to determine the potential risk factors and outcomes of shunt-dependent hydrocephalus in aneurysmal SAH patients but without hydrocephalus upon arrival at the hospital.
One hundred and sixty-eight aneurysmal SAH patients were evaluated. Using functional scores, those without hydrocephalus upon arrival at the hospital were compared to those already with hydrocephalus on admission, those who developed it during hospitalization, and those who did not develop it throughout their hospital stay. The Glasgow Coma Score, modified Fisher SAH grade, and World Federation of Neurosurgical Societies grade were determined at the emergency room. Therapeutic outcomes immediately after discharge and 18 months after were assessed using the Glasgow Outcome Score.
Hydrocephalus accounted for 61.9% (104/168) of all episodes, including 82 with initial hydrocephalus on admission and 22 with subsequent hydrocephalus. Both the presence of intra-ventricular hemorrhage on admission and post-operative intra-cerebral hemorrhage were independently associated with shunt-dependent hydrocephalus in patients without hydrocephalus on admission. After a minimum 1.5 years of follow-up, the mean Glasgow outcome score was 3.33 ± 1.40 for patients with shunt-dependent hydrocephalus and 4.21 ± 1.19 for those without.
The presence of intra-ventricular hemorrhage, lower mean Glasgow Coma Scale score, and higher mean scores of the modified Fisher SAH and World Federation of Neurosurgical grading on admission imply risk of shunt-dependent hydrocephalus in patients without initial hydrocephalus. These patients have worse short- and long-term outcomes and longer hospitalization.
PMCID: PMC3467164  PMID: 22765765
Outcome; Risk factors; Hydrocephalus after spontaneous aneurysmal subarachnoid hemorrhage
18.  Plasma nuclear and mitochondrial DNA levels as predictors of outcome in severe sepsis patients in the emergency room 
Background and aim
The sensitivity and specificity of biomarkers and scoring systems used for predicting fatality of severe sepsis patients remain unsatisfactory. This study aimed to determine the prognostic value of circulating plasma DNA levels in severe septic patients presenting at the Emergency Department (ED).
Sixty-seven consecutive patients with severe sepsis and 33 controls were evaluated. Plasma DNA levels were estimated by real-time quantitative polymerase chain reaction assay using primers for the human β-hemoglobin and ND2 gene. The patients’ clinical and laboratory data on admission were analyzed.
The median plasma nuclear and mitochondria DNA levels for severe septic patients on admission were significantly higher than those of the controls. The mean plasma nuclear DNA level on admission correlated with lactate concentration (γ = 0.36, p = 0.003) and plasma mitochondrial DNA on admission (γ = 0.708, p < 0.001). Significant prognostic factors for fatality included mechanical ventilation within the first 24 hours (p = 0.013), mean sequential organ failure assessment (SOFA) score on admission (p = 0.04), serum lactate (p < 0.001), and both plasma nuclear and mitochondrial DNA on admission (p < 0.001). Plasma mitochondrial DNA was an independent predictor of fatality by stepwise logistic regression such that an increase by one ng/mL in level would increase fatality rate by 0.7%.
Plasma DNA has potential use for predicting outcome in septic patients arriving at the emergency room. Plasma mitochondrial DNA level on admission is a more powerful predictor than lactate concentration or SOFA scores on admission.
PMCID: PMC3441240  PMID: 22720733
Hospital mortality; Mitochondrial DNA; Nucleus DNA; Severe sepsis
19.  Connectivity of Default-Mode Network Is Associated with Cerebral Edema in Hepatic Encephalopathy 
PLoS ONE  2012;7(5):e36986.
Cerebral edema, a well-known feature of acute liver disease, can occur in cirrhotic patients regardless of hepatic encephalopathy (HE) and adversely affect prognosis. This study characterized and correlated functional HE abnormalities in the brain to cerebral edema using resting-state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI). Forty-one cirrhotic patients (16 without HE, 14 minimal HE, 11 overt HE) and 32 healthy controls were assessed. The HE grade in cirrhotic patients was evaluated by the West Haven criteria and neuro-psychological examinations. Functional connectivity correlation coefficient (fc-CC) of the default mode network (DMN) was determined by rs-fMRI, while the corresponding mean diffusivity (MD) was obtained from DTI. Correlations among inter-cortical fc-CC, DTI indices, Cognitive Ability Screening Instrument scores, and laboratory tests were also analyzed. Results showed that gradual reductions of HE-related consciousness levels, from “without HE” or “minimal HE” to “overt HE”, correlated with decreased anterior-posterior fc-CC in DMN [F(4.415), p = 0.000)]. The MD values from regions with anterior-posterior fc-CC differences in DMN revealed significant differences between the overt HE group and other groups. Increased MD in this network was inversely associated with decreased fc-CC in DMN and linearly correlated with poor cognitive performance. In conclusion, cerebral edema can be linked to altered cerebral temporal architecture that modifies both within- and between-network connectivity in HE. Reduced fc-CC in DMN is associated with behavior and consciousness deterioration. Through appropriate targets, rs-fMRI technology may provide relevant supplemental information for monitoring HE and serve as a new biomarker for clinical diagnosis.
PMCID: PMC3356373  PMID: 22623966
20.  Impaired Small-World Network Efficiency and Dynamic Functional Distribution in Patients with Cirrhosis 
PLoS ONE  2012;7(5):e35266.
Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome and a major complication of liver cirrhosis. Dysmetabolism of the brain, related to elevated ammonia levels, interferes with intercortical connectivity and cognitive function. For evaluation of network efficiency, a ‘small-world’ network model can quantify the effectiveness of information transfer within brain networks. This study aimed to use small-world topology to investigate abnormalities of neuronal connectivity among widely distributed brain regions in patients with liver cirrhosis using resting-state functional magnetic resonance imaging (rs-fMRI). Seventeen cirrhotic patients without HE, 9 with minimal HE, 9 with overt HE, and 35 healthy controls were compared. The interregional correlation matrix was obtained by averaging the rs-fMRI time series over all voxels in each of the 90 regions using the automated anatomical labeling model. Cost and correlation threshold values were then applied to construct the functional brain network. The absolute and relative network efficiencies were calculated; quantifying distinct aspects of the local and global topological network organization. Correlations between network topology parameters, ammonia levels, and the severity of HE were determined using linear regression and ANOVA. The local and global topological efficiencies of the functional connectivity network were significantly disrupted in HE patients; showing abnormal small-world properties. Alterations in regional characteristics, including nodal efficiency and nodal strength, occurred predominantly in the association, primary, and limbic/paralimbic regions. The degree of network organization disruption depended on the severity of HE. Ammonia levels were also significantly associated with the alterations in local network properties. Results indicated that alterations in the rs-fMRI network topology of the brain were associated with HE grade; and that focal or diffuse lesions disturbed the functional network to further alter the global topology and efficiency of the whole brain network. These findings provide insights into the functional changes in the human brain in HE.
PMCID: PMC3341390  PMID: 22563460
21.  White Matter Abnormalities Correlating with Memory and Depression in Heroin Users under Methadone Maintenance Treatment 
PLoS ONE  2012;7(4):e33809.
Methadone maintenance treatment (MMT) has elevated rates of co-morbid memory deficit and depression that are associated with higher relapse rates for substance abuse. White matter (WM) disruption in MMT patients have been reported but their impact on these co-morbidities is unknown. This study aimed to investigate changes in WM integrity of MMT subjects using diffusion tensor image (DTI), and their relationship with history of heroin and methadone use in treated opiate-dependent individuals. The association between WM integrity changes from direct group comparisons and the severity of memory deficit and depression was also investigated. Differences in WM integrity between 35 MMT patients and 23 healthy controls were evaluated using DTI with tract-based spatial statistical analysis. Differences in DTI indices correlated with diminished memory function, Beck Depression Inventory, duration of heroin use and MMT, and dose of heroin and methadone administration. Changes in WM integrity were found in several WM regions, including the temporal and frontal lobes, pons, cerebellum, and cingulum bundles. The duration of MMT was associated with declining DTI indices in the superior longitudinal fasciculus and para-hippocampus. MMT patients had more memory and emotional deficits than healthy subjects. Worse scores in both depression and memory functions were associated with altered WM integrity in the superior longitudinal fasciculus, para-hippocampus, and middle cerebellar peduncle in MMT. Patients on MMT also had significant WM differences in the reward circuit and in depression- and memory-associated regions. Correlations among decreased DTI indices, disease severity, and accumulation effects of methadone suggest that WM alterations may be involved in the psychopathology and pathophysiology of co-morbidities in MMT.
PMCID: PMC3322116  PMID: 22496768
22.  The association between serum adhesion molecules and outcome in acute spontaneous intracerebral hemorrhage 
Critical Care  2011;15(6):R284.
Serum concentrations of adhesion molecules may be connected to the pathogenesis of secondary brain injury after spontaneous intracerebral hemorrhage (ICH). This study posits the hypothesis that levels of adhesion molecules substantially increase after ICH and are decreased thereafter, and that they can predict treatment outcomes.
Two hundred and thirty-nine blood samples were collected from 60 consecutive patients admitted within 24 hours after onset of spontaneous ICH and 60 blood samples were collected from 60 volunteers. Additional samples were obtained on Days 4, 7, 10, and 14 after onset of ICH regardless of clinical deterioration.
Upon discharge, the therapeutic outcomes of the 60 spontaneous ICH cases based on the modified Rankin Disability Scale (mMRS) showed that 17 had no disability while 8.3% developed delayed cerebral infarction (DCI). Statistical analysis of adhesion molecules between patient groups with good outcome (mMRS = 0 or 1) and poor outcome (mMRS ≥2) revealed significant differences in diabetes mellitus (P=0.049), hyperlipidemia (P=0.012), mentality change (P=0.043), ICH volume and intraventricular hemorrhage on admission (P=0.036 and 0.006, respectively), Glasgow Coma Scale (GCS) on admission (P≤0.001), neuro-surgical intervention (P=0.003), and sE-selectin and soluble intercellular cell adhesion-molecule-1 (sICAM-1) levels on admission (P=0.036 and 0.019, respectively). Multiple logistic regression analysis of these significant variables showed that GCS on admission, hyperlipidemia, and sICAM-1 (P=0.039, 0.042, and 0.022, respectively) were independently associated with outcome of acute spontaneous ICH.
Increased sICAM-1 and sE-selectin levels may imply poor therapeutic outcomes for the treatment of spontaneous ICH during hospitalization. These early inflammatory responses may cause whole-brain injury immediately after spontaneous ICH and offer a potential therapeutic target for such patients. The importance of these findings is that they offer a potential therapeutic target for patients with spontaneous ICH.
PMCID: PMC3388671  PMID: 22117900
23.  The impact of preoperative magnetic resonance images on outcome of cemented vertebrae 
European Spine Journal  2010;19(11):1899-1906.
Refracture of cemented vertebrae is often seen after percutaneous vertebroplasty. The purpose of this prospective study was to evaluate pre-procedural magnetic resonance images (MRI) for the prediction of further collapse and vertebral height loss after vertebroplasty. This study included 81 consecutive patients (73 women and 8 men) with osteoporotic compression fractures. MR studies were performed 1–5 days before vertebroplasty. Patients were followed to evaluate refracture for a minimum of 6 months after treatment. Cox proportional hazards model was used to evaluate relationships between clinical data, covariates on pre-procedural MRI, and the presence of cemented vertebrae refracture. The mean refracture rate was estimated with the Kaplan–Meier method. After a mean follow-up of 23.0 ± 8.2 months, 46 cemented vertebrae (57%) experienced refracture, and the mean loss of anterior vertebral height was 11.3%. The 1-year refracture rate after vertebroplasty was 7%, and rapid increased to 76% in the third year. Cox proportional analysis showed that any 1% decrease in signal intensity on T2-weighted images of the injured vertebra will increase the refracture rate by 0.74% (OR = 0.26, 95% CI 0.08–0.81, p = 0.02), and a 1% increase in the poorly enhanced volume ratio will increase the refracture rate by 4.3% (OR = 5.32, 95% CI 1.22–23.14, p = 0.03). Quantitative pre-procedural MRI appears to be useful in exploring vertebrae with poor bone marrow integrity, which effectively predicts the subsequent refracture of cemented vertebra.
PMCID: PMC2989252  PMID: 20607571
Magnetic resonance imaging; Osteoporosis; Spine; Vertebral fracture; Vertebroplasty
24.  Statin pre-treatment is associated with lower platelet activity and favorable outcome in patients with acute non-cardio-embolic ischemic stroke 
Critical Care  2011;15(4):R163.
Statins reportedly have anti-inflammatory and anti-thrombotic effects aside from cholesterol-lowering. This study aimed to evaluate the effect of pre-existing statin use on platelet activation markers and clinical outcome in acute ischemic stroke patients.
This prospective study evaluated 172 patients with acute ischemic stroke divided in two groups: patients with pre-existing statin (n = 43) and without pre-existing statin (66 cases with statins initiated post-stroke and 63 without statin treatment). Platelet activation markers (CD62P and CD63) were measured by flow cytometry at different time points after stroke and analyzed with clinical outcome.
The CD62P and CD63 expressions on platelets were significantly lower in the patients with pre-existing statin use compared to the patients without pre-existing statin use on Day 1 post-stroke (p < 0.05). The CD62P expression was significantly lower in the patients with pre-existing statin use on 90 days after the acute stroke (p < 0.05). Patients with pre-existing statin use had lower incidences of early neurologic deterioration (END) than those without treatment (p < 0.05). Among several baseline clinical variables, admission NIHSS score, history of coronary artery disease, and pre-existing statin use were independent predictions of good clinical outcome at three months.
Pre-existing statin use is associated with decreased platelet activity as well as improved clinical outcome and reduced END in patients with acute ischemic stroke.
PMCID: PMC3387600  PMID: 21740551
flow cytometry; ischemic stroke; outcome; platelet activation
25.  Refractures in cemented vertebrae after percutaneous vertebroplasty: a retrospective analysis 
European Spine Journal  2008;17(4):592-599.
Percutaneous vertebroplasty is an efficient procedure to treat pain due to osteoporotic vertebral compression fractures. However, refracture of cemented vertebrae occurs occasionally after vertebroplasty. It is unclear whether such fractures are procedure-related or part of the natural course of osteoporosis. The effect of potentially important covariates on refracture risk in cemented vertebrae has not been evaluated previously. We retrospectively analyzed the incidence and possible causative mechanism of refracture in patients who had received only one vertebroplasty for a single level of vertebral compression fracture. We assessed the following covariates: age, sex, body weight, height, lumbar spine bone mineral density, treated vertebral level, pre-existing untreated vertebral compression fracture, and gas-containing vertebrae before treatment. Surgical variables, including surgical approach, cement injected, and anterior vertebral height restoration, were also analyzed. Anti-osteoporotic treatment after surgery was recorded. Multiple logistic regression analysis was used to determine the relative risk of refractures of cemented vertebrae. Over all, 98 patients were evaluated with a mean follow-up of 26.9 ± 12.4 months (range, 7–55 months). We identified 62 refractures and the mean loss of anterior vertebral height was 13.3% (range 3.2–40.3%). The greater the anterior vertebral height obtained from vertebroplasty, the greater the risk of refracture occurring (P < 0.01). Gas-containing vertebrae were also prone to refracture after the procedure (P = 0.01). Anti-osteoporotic treatment was of borderline significance between refractured and non-refractured vertebrae (P = 0.07). Only restoration of anterior vertebral height was positively associated with refracture during the follow-ups (P < 0.01). In conclusion, refractures of cemented vertebrae after vertebroplasty occurred in 63% of osteoporotic patients. Significant anterior vertebral height restoration increases the risk of subsequent fracture in cemented vertebrae.
PMCID: PMC2295276  PMID: 18204942
Compression fracture; Osteoporosis; Refracture; Vertebral height; Vertebroplasty

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